Silvana Molossi

In vivo blockade of tumor necrosis factor-alpha in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation.

BACKGROUND We previously identified in piglet cardiac allografts an immunoinflammatory response in coronary arteries in which increased fibronectin regulated by interleukin-1 beta was associated with early evidence of intimal thickening. In the present study, we used rabbits to assess whether acute neointimal formation after cardiac transplantation was reduced by blockade of tumor necrosis factor (TNF)-alpha, which modulates interleukin-1 beta, or by cyclosporine A. METHODS AND RESULTS Sixteen rabbits underwent heterotopic cardiac transplantation and were given saline, TNF-soluble receptor (sr), or cyclosporine A. In host hearts from saline- or TNFsr-treated groups, few coronary arteries (approximately 13% to 16%) had intimal thickening, whereas values were higher in the cyclosporine A-treated group (approximately 30%). In donor hearts from the saline-treated group, however, approximately 68% of vessels had intimal thickening versus approximately 32% in TNFsr- and approximately 30% in cyclosporine A-treated groups (P < .01 for both). Severity of intimal thickening assessed quantitatively as percent vessel area was approximately 38% in the saline-treated group but reduced in TNFsr- and cyclosporine A-treated groups to approximately 22% and 18%, respectively (P < .01 for each). Immunohistochemistry revealed increased staining for major histocompatibility complex II, T cells, interleukin-1 beta, TNF-alpha, and fibronectin in donor coronary arteries from saline-treated animals when compared with TNFsr- and cyclosporine A-treated animals. Grade 3 myocardial rejection was observed in both saline- and TNFsr-treated groups, but only grade 1 was apparent in the cyclosporine A-treated group. CONCLUSIONS In vivo blockade of TNF-alpha suppresses the acute development of neointimal formation by selectively reducing the vascular immunoinflammatory reaction and accumulation of fibronectin, whereas cyclosporine A suppresses both the myocardial and the vascular immune reaction.

Expression of tumour necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesions retrieved by atherectomy.

BACKGROUND--The formation of coronary artery neointima experimentally induced in piglets after cardiac transplantation is related to an immune-inflammatory reaction associated with increased expression of T cells and inflammatory mediators (tumour necrosis factor alpha and interleukin 1 beta) and upregulation of fibronectin. In vivo blockade of tumour necrosis factor alpha in rabbits after cardiac transplantation results in reduced neointimal formation. The objective of this study was to investigate the hypothesis that coronary restenosis after atherectomy or percutaneous balloon angioplasty is associated with a similar inflammatory cascade initiated by mechanical injury. METHODS--Specimens taken at coronary atherectomy were analysed from 16 patients. Nine had had the procedure performed twice, firstly, to remove a primary lesion, and secondly, to remove a restenotic lesion. Seven had percutaneous balloon angioplasty after removal of restenotic tissue. Coronary atherectomy specimens were analysed by immunohistochemistry for the presence of T cells, macrophages, major histocompatibility complex II, interleukin 1 beta, tumour necrosis factor alpha, fibronectin, and the receptor for hyaluronan mediated motility. RESULTS--The groups were clinically and angiographically similar with equivalent lumens before and after atherectomy. Restenotic lesions had increased expression of tumour necrosis factor alpha and fibronectin compared with the primary lesions (P < 0.05 for both). There was also a trend towards a greater number of T cells and increased expression of interleukin 1 beta. CONCLUSIONS--Restenosis is associated with increased expression of tumour necrosis factor alpha and fibronectin, suggesting that an immune-inflammatory reaction probably contributes to neointimal formation and may represent a form of wound healing and repair secondary to mechanical injury.

International recommendations for electrocardiographic interpretation in athletes

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On February 26-27, 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries

OBJECTIVES We sought to determine whether abnormalities in small intramyocardial vessels could be detected on routine cardiac transplant biopsy specimens and whether these features correlate with intimal thickening by intracoronary ultrasound and endothelial dysfunction in large epicardial vessels. BACKGROUND Variability in clinical presentation of allograft vasculopathy suggests differential involvement of large and small vessels. Intracoronary ultrasound and endothelial function studies detect large-vessel abnormalities but may not reflect changes in small intramyocardial arteries. The latter could be detected in routine cardiac biopsy specimens by histologic and immunohistochemical studies. METHODS Thirty-nine cardiac transplant recipients underwent intracoronary ultrasound and acetylcholine studies 5 to 7 days after endomyocardial biopsy. Biopsy tissue was evaluated for coronary artery endothelial plumping and intimal thickening and increased immunostaining for fibronectin, tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility. Large-vessel disease was assessed by calculating an average intimal index from intracoronary ultrasound of the left anterior descending coronary artery. Endothelial function was determined by quantitative coronary analysis after acetylcholine challenge. RESULTS Coronary arteries were found in the biopsy tissue of 30 (76%) of the 39 patients who formed the study group. Fourteen of 30 patients had abnormal histologic findings. Immunohistochemical analysis for fibronectin, possible in 20 of 30 patients, was positive in 14 (70%) of 20 and correlated with abnormal histologic findings (p = 0.01). Immunostaining was positive for tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility in 12 (40%) and 13 (43%) of 30 patients, respectively. All patients had intimal thickening by intracoronary ultrasound, but intimal index did not correlate significantly with small-artery disease by histologic or immunohistochemical analysis. Large-vessel endothelial dysfunction in 13 patients (43%) did not correlate with either abnormal ultrasound findings or small-vessel disease. CONCLUSIONS Intramyocardial arteries are readily observed in biopsy specimens from cardiac transplant recipients and provide useful information about allograft vasculopathy. Lack of correlation between intramyocardial and epicardial vessel disease suggests discordant progression of allograft vasculopathy.

Interassociation Consensus Statement on Cardiovascular Care of College Student-Athletes

Cardiovascular evaluation and care of college student-athletes is gaining increasing attention from both the public and medical communities. Emerging strategies include screening of the general athlete population, recommendations of permissible levels of participation by athletes with identified cardiovascular conditions, and preparation for responding to unanticipated cardiac events in athletic venues. The primary focus has been sudden cardiac death and the utility of screening with or without advanced cardiac screening. The National Collegiate Athletic Association convened a multidisciplinary task force to address cardiovascular concerns in collegiate student-athletes and to develop consensus for an interassociation statement. This document summarizes the task force deliberations and follow-up discussions, and includes available evidence on cardiovascular risk, pre-participation evaluation, and the recognition of and response to cardiac arrest. Future recommendations for cardiac research initiatives, education, and collaboration are also provided.

International criteria for electrocardiographic interpretation in athletes: consensus statement

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26–27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Pulmonary blood supply by a branch from the distal ascending aorta in pulmonary atresia with ventricular septal defect: Differential diagnosis of fifth aortic arch

SummaryA patient with pulmonary atresia and a ventricular septal defect is described in whom an arterial branch from the distal ascending aorta supplied segments of both lungs. The branch is considered to represent a persistent fifth aortic arch. The possible morphogenesis and differential diagnosis of a communication between the ascending aorta and the pulmonary artery in pulmonary atresia with ventricular septal defect are discussed.

Outcomes of surgical intervention for anomalous aortic origin of a coronary artery: A large contemporary prospective cohort study

Objective The purpose of this study was to prospectively analyze the outcomes of patients with anomalous aortic origin of a coronary artery undergoing surgical intervention according to a standardized management algorithm. Methods All patients aged 2 to 18 years undergoing surgical intervention for anomalous aortic origin of a coronary artery between December 2012 and April 2017 were prospectively included. Patients underwent stress nuclear perfusion imaging, stress cardiac magnetic resonance imaging, and retrospectively electrocardiogram‐gated computed tomography angiography preoperatively. Patients were cleared for exercise at 3 months postoperatively if asymptomatic and repeat stress nuclear perfusion imaging, stress cardiac magnetic resonance imaging, and computed tomography angiography showed normal results. Results A total of 44 patients, with a median age of 14 years (8‐18 years), underwent surgical intervention: 9 (20%) for the anomalous left coronary artery and 35 (80%) for the anomalous right coronary artery. Surgical procedures included unroofing in 35 patients (80%), translocation in 7 patients (16%), ostioplasty in 1 patient (2%), and side‐side‐anastomosis in 1 patient (2%). One patient who presented with aborted sudden cardiac death from an anomalous left coronary and underwent unroofing presented 1 year later with a recurrent episode and was found to have an unrecognized myocardial bridge and persistent compression of the coronary requiring reintervention. At last follow‐up, 40 patients (91%) are asymptomatic and 4 patients have nonspecific chest pain; 42 patients (95%) have returned to full activity, and 2 patients are awaiting clearance. Conclusions Surgical treatment for anomalous aortic origin of a coronary artery is safe and should aim to associate the coronary ostium with the correct sinus, away from the intercoronary pillar. After surgery, the majority of patients are cleared for exercise and remain asymptomatic. Longer follow‐up is needed to assess the true efficacy of surgery in the prevention of sudden cardiac death.

Histological and Immunohistochemical Characteristics of Eccentric Coronary Artery Lesions Retrieved by Atherectomy from Cardiac Transplant Recipients

The lesions of cardiac allograft vasculopathy are thought to be strongly related to an immune inflammatory process. Little is known about the biology of these eccentric lesions. However, transplant patients may present with focal disease. Coronary atherectomy provides a unique opportunity to study these clinically relevant lesions in surviving transplant patients. In this series we characterized the features of four lesions (two restenotic and two primary) from three cardiac transplant recipients who underwent coronary atherectomy. The histologic characteristics of the lesions were analyzed and immunohistochemistry was used to assess qualitatively the presence of specific markers of inflammation and the extracellular matrix component fibronectin. Histology showed cholesterol clefts, calcium deposits, and foam cells with low to moderate cellularity and moderate to high fibrosis. Interleukin (IL)-1β was present in two lesions, but tumor necrosis factor (TNF)-α was absent. The adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cellular adhesion molecule (VCAM)-1 and the integrins α5β1 and α4 were present in all lesions. There was mild to moderate accumulation of fibronectin. Thus, atheroscleroticlike features were present with only low to moderate degrees of immune inflammation. Our findings suggest that eccentric focal plaques in cardiac allograft vasculopathy are less likely to be primarily related to a prominent immune inflammatory process and are similar to atherosclerosis. We speculate that these eccentric lesions that resemble atherosclerosis may be more related to the conventional risk factors for coronary artery disease frequently seen in this population.

Analysis of atherosclerotic plaques obtained by coronary atherectomy: Foam cells correlated positively with subsequent restenosis

Restenosis following coronary intervention is a complex process the mechanisms of which remains mostly unknown. Tissue obtained by atherectomy is an important means to study restenosis. Previous studies on atherectomy-retrieved tissue have not identified histologic features that correlate with restenosis. We performed an histopathologic evaluation on atherosclerotic plaque tissue obtained by atherectomy from 58 patients, all of whom had a 6-month angiographic follow-up. We identified macrophages and lymphocytes and localized tumor necrosis factor-α expression in the tissue by immunohistochemistry. Histopathology was correlated with late angiographic outcomes. Of 10 histologic features evaluated in the plaque tissue, only the presence of foam cells, identified in paraffin sections, correlated positively with restenosis (p = 0.04). Immunohistochemistry showed that macrophages (p = .07), tumor necrosis factor-α (p = .07), and lymphocytes (p = .14) were more prominent, but not significantly so, in lesions from patients with foam cells and restenosis than in lesions from patients without foam cells or restenosis. Thus the presence of foam cells in primary lesions obtained by atherectomy as identified in paraffin-embedded tissue appears to be a marker for restenosis.